Het(aryl)isatin to het(aryl)aminoindoline scaffold hopping: A route to selective inhibitors of matrix metalloproteinases

Matrix metalloproteinases (MMPs) are a large family of zinc-dependent endoproteases known to exert multiple regulatory roles in tumor progression. A variety of chemical classes have been explored for targeting individual MMP isoforms. In the present study, we further developed our isatin based scaffold BB0223107 capable of binding to and inactivating MMP-2 in a zinc-independent manner (Agamennone et al., 2016). Forty four new compounds were synthesized based on the modified BB0223107. All compounds were tested in enzyme inhibition assays against MMP-2, ?8 and ?13. SAR studies demonstrated that 5-het(aryl)-3-aminoindolin-2-ones (37–39) were active toward MMP-2 and MMP-13. The most potent compounds 33 and 37 displayed an IC₅₀ of 3 µM against MMP-13 and showed a negligible activity toward MMP-8; almost all new compounds were inactive toward MMP-8. Replacement of the isatin ring with a biaryl system (compound 33) did not decrease the potency against MMP-13 but reduced the selectivity. Structure-based computational studies were carried out to rationalize the inhibitory activity data. The analysis of binding geometries confirmed that all fragments occupied the S1′ site in the three enzymes while no ligand was able to bind the catalytic zinc ion. To the best of our knowledge, this is the first example of 3-aminoindolin-2-one-based MMP inhibitors that, based on the computer modeling study, do not coordinate the zinc ion. Thus, the het(aryl)-3-aminoindolin-2-one derivatives emerge as a drug-like and promising chemotype that, along with the hetaryl variations, represents an alternative and thrifty tool for chemical space exploration aimed at MMP inhibitor design.     

An improved synthesis of isonitrosoacetanilides

A novel two-step synthesis of isonitrosoacetanilides [2-(hydroxyimino)-N-phenylacetamides] has been developed, involving the initial acylation of aniline derivatives with 2,2-diacetoxyacetyl chloride, followed by reaction with hydroxylamine hydrochloride. The method works equally well with a variety of different aniline derivatives, including those with poor aqueous solubility and those containing electron rich ortho-substituents, neither of which react well under traditional conditions.     

New Approach to Synthesis of 6,7—Dimethoxyisatin

A new approach to synthesis of 6,7-dimethoxyisatin is reported.2-nitro-3,4-dimethoxy mandelonitrile in glacial acetic acid was treated with the solution of stannous chloride in hydrochloric acid to give 6,7-dimethoxyisatin in a high yield.     

A novel multicomponent reaction involving isoquinoline,allenoate and activated ketone

The reaction of isoquinoline and allenoate with activated ketone resulted in a novel three component reaction, affording [1,3]oxazino[2,3-a]isoquinoline derivatives in moderate yields along with moderate diastereoselectivities via 1,4-dipolar cycloaddition. It was also found that when isatins were used as substrates, the regioselectivity of cycloadducts was different from those using ethyl trifluoropyruvate as substrate.     

有机催化吲哚碳环上的不对称Friedel⁃Crafts烷基化反应

将金鸡纳碱衍生物双功能催化剂用于有机催化羟基吲哚与靛红的不对称Friedel-Crafts反应, 筛选出最佳反应条件: 催化剂为5%(摩尔分数)6′-脱甲基奎尼丁(1b), 溶剂为四氢呋喃, 反应温度 0 ℃. 以67%~91%的产率和最高达97%的对映选择性获得了苯环上取代的羟基烷基化产品. 拓宽了该反应的催化剂类型和底物范围.     

Group 6 metal carbonyl complexes of 3′H-spiro[indole-3,2′-[1,3]benzothiazole-2(1H)]-one

The spiro-compound 3′H-spiro[indole-3,2′-[1,3]benzothiazole-2(1H)-one (IBTH₂) was synthesized and its structure was determined using spectroscopic techniques (FTIR, ¹H NMR and mass) and X-ray crystallography. This ligand possesses different centers for coordination. Reactions of [M(CO)₆], M = Cr, Mo or W with IBTH₂ in THF under reduced pressure were studied. For chromium a complex with molecular formula [Cr(ITP)₂] was isolated; where ITP is the opened form of the ligand which occurred through C_spiro–S bond, while [Mo(CO)₅(IBTH₂)] and [W(CO)₅(IBTH₂)] were isolated from the reaction of IBTH₂ with molybdenum and tungsten carbonyls, respectively. All complexes were characterized by elemental analysis, IR, mass and ¹H NMR spectroscopy. The biological activity of the ligand and its complexes were studied and compared with the parent compound isatin.     

Cascade synthesis of selective dihydro pyridazino fused acridinone derivatives via MCM-41 catalyzed ring-opening/ring-closure reaction

An enhanced one-pot synthesis of new functionalized 5,6-dihydro-5,5-dimethyl-2-phenyl-2H-pyridazino[3,4,5-kl]acridin-1(4H)-one derivatives with different substituted patterns by using mesoporous MCM-41 catalyst via a ring opening/ring closure reaction process has been established. This MCM-41 silica catalyst has been synthesized and characterized using an array of sophisticated analytical techniques like BET, XRD, UHRTEM, etc. This reaction could be conducted from inexpensive substrates within short period under neat reflux conditions. Compared with the usual methods, the remarkable advantages of this method are milder reaction conditions, operational simplicity, higher yields, short reaction times and an environmentally friendly procedure.     

Synthesis of polysubstituted 5-hydroxyhydantoins via ring-opening of isatins

A simple and efficient tandem reaction approach was developed for the synthesis of 5-hydroxyhydantoins from one-pot reaction of isatins, phthalic anhydride or succinic anhydride, and 1,3-dimethylurea (1,3-diethylurea). The products were gained through the ring-opening of isatins process. The advantages of this report are simple operation, mild reaction conditions, good yields and easily available raw materials. It was very important for us to obtain the intermediate product and that provided a solid basis for the correct interpretation of the reaction mechanism.     

One step synthesis of indirubins by reductive coupling of isatins with KBH4

One step synthesis of the natural product indirubin by reductive coupling of isatin with KBH₄ is described and a possible mechanism for the reaction is proposed. Eleven indirubin derivatives were obtained easily from the corresponding substituted isatin.     

Synthesis of symmetrical and unsymmetrical 3,3-di(indolyl)indolin-2-ones under controlled catalysis of ionic liquids

Three ionic liquids, [BMIM][BF₄] doped with 60 mol % of LiCl ([BMIM][BF₄]-LiCl), N,N,N,N-tetramethylguanidinium trifluoroacetate (TMGT), and N,N,N,N-tetramethylguanidinium triflate (TMGT_f) were found useful as catalyst solvents for controlled 3-indolylation of isatins. Our investigation revealed that the reaction between isatin and indoles in [BMIM][BF₄]-LiCl or TMGT_f media stops at the step of addition of the two components providing 3-indolyl-3-hydroxyindolin-2-ones while the ionic liquid TMGT runs the reaction further through accompanying Friedel-Crafts substitution to afford symmetrical 3,3-di(indol-3-yl)indolin-2-ones. To take advantage of the difference between the effects of these ionic liquids on the reaction progress, we planned a two-step protocol for the efficient synthesis of unsymmetrical 3,3-di(indol-3-yl)indolin-2-ones.